Design, Synthesis, and Biological Activity of a Difluoro-Substituted, Conformationally Rigid Vigabatrin Analogue as a Potent γ-Aminobutyric Acid Aminotransferase Inhibitor

Abstract

Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate gamma-aminobutyric acid aminotransferase (GABA-AT). A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mercaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.

A New Inhibitor of γ-aminobutric Acid Aminotransferase from Streptomyces sp. ZZ035 Isolated from a Folk Medicinal Soil in China

“…As GABA-AT is a key enzyme involved in the GABA metabolic pathways and GABA shunt, the inhibitors of this enzyme can increase the level of GABA, and have a potency to cure some diseases derived from the decrease of GABA. After vigabatrin was used as an irreversible GABA-AT inhibitor to cure epilepsy in clinic [18] , many other GABA analogs were synthesized for the inhibitory evaluation of GABA-AT [16,[19][20][21][22][23][24][25][26][27] . Moreover, gabaculine, a naturally occurring neurotoxin produced by the bacteria Streptomyces toyocaensis No.…”

“…5) according to previous works [16,[19][20][21][24][25][26][27] , and all of them were GABA-AT inhibitors. Among approximately sixty GABA derivatives reported, no 2,3-disubstituted GABA derivatives (Fig.…”

Bicyclic γ-amino acids as inhibitors of γ-aminobutyrate aminotransferase

“…Surprisingly, the GABA cyclic analogue 1 does not inactivate GABA-AT but behaves as a substrate, and this was explained by computer modeling as the result of an improper positioning of the double bond in the ring with respect to the "-amino group of Lys329 18 . On the contrary, derivative 2, characterized by the presence of a difluorovinyl moiety, turned out to be an extremely potent GABA-AT inhibitor, 52 times more potent than Vigabatrin itself, when assayed under suboptimal conditions 15 . This result has been accounted for by considering the mechanism of inactivation, which implies the initial formation of an imine adduct between the amine group of 2 and PLP, followed by the nucleophilic attack of Lys329 at the distal carbon of the methylenyl double bond, favored by the presence of two electron-withdrawing fluorine atoms on the double bond itself 19 .…”

“…Because to date there are no activating molecules that selectively enhance the activity of GAD67, the major GAD isoform involved in GABA synthesis in the CNS, an alternative strategy to achieve an increase in GABA levels consists in the effective inhibition of the major GABAdegradative enzyme, i.e., GABA aminotransferase (GABA-AT, E.C. 2.6.1.19) [13][14][15] . Both GAD and GABA-AT are pyridoxal 5 0 -phosphate (PLP)-dependent enzymes, but localized in different compartments, the former in the cytosol and the latter in the mitochondrial matrix.…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…Debromination and hydrolysis of (557) furnishes the 3-hydroxy derivative (565) which can be converted to the 3-bromo amino acid (566) [384]. Finally the ketone (559) can be converted to alkenes by reaction with fluoromethyl phenylsulfone to yield (567a) [386] or via Horner-Wadsworth-Emmons reactions to yield (567b and c) [387].…”